The long-range goals of this project are: (1)\to elucidate, at the molecular level, pathogenetic mechanisms involved in the uncontrolled growth of human gliomas and (2)\to find means of correcting these abnormalities in ways that could be applied clinically. We have found that human natural killer (NK) cells can lyse some human fetal brain and glioma cell lines but the majority are resistant. This resistance is due to impaired effector-target cell binding in some and target lysis in others, while another group has a combination of both factors. Exposure of effector cells to interferon augments their activity against these neural cells, while exposure of targets makes them more resistant. Interferon treatment of neural target cells also increases their neutral glycolipid contents and in some produces shifts of their glycolipid profiles so that there is proportionately more complex and less simple neutral glycolipid. Therefore, neutral glycolipids may be involved in determining the sensitivity and/or resistance of cells to NK cytolysis. We are currently analyzing the gangliosides of these cells to see if they correlate with target cell sensitivity to NK. To determine more precisely the correlation between NK sensitivity of glioma targets and their glycolipid composition, we must alter the glycolipids in different ways and determine if there is a consistent change in NK target binding and/or lysis. To do this, we will treat the cultured glioma cells with agents that alter either their glycolipid composition or degree of cellular differentiation and monitor their binding to and lysis by NK cells and their glycolipid compositions. This information should indicate which specific glycolipids are involved in molecular mechanisms responsible for recognition, binding, and/or lysis of human gliomas by NK cells. (LB)